Surgical Resection Margin Classifications for High

Modern Pathology (2019) 32:1421–1433 https://doi.org/10.1038/s41379-019-0278-9

ARTICLE

Surgical resection margin classiﬁcations for high-grade pleomorphic soft tissue sarcomas of the extremity or trunk: deﬁnitions of adequate resection margins and recommendations for sampling margins from primary resection specimens

1 2 Margaret M. Cates ● Justin M. M. Cates

Received: 4 February 2019 / Revised: 29 March 2019 / Accepted: 30 March 2019 / Published online: 3 May 2019 © United States & Canadian Academy of Pathology 2019

Abstract Adequacy of surgical resection margins for soft tissue sarcomas are poorly defined because of the various classifications and definitions used in prior studies of heterogeneous patient cohorts and inconsistent margin sampling protocols. Surgical resection margins of 166 primary, high-grade, pleomorphic sarcomas of the extremity or trunk were classified according to American Joint Committee on Cancer R and Musculoskeletal Tumor Society categories, as well as by metric distance and tissue composition. None of the cases were treated with neoadjuvant therapy. Multivariable competing risk regression 1234567890();,: 1234567890();,: models were evaluated and optimal surgical resection margins for each classification system were defined. Minimum safe tumor clearance was 5 mm without use of adjuvant radiotherapy and 1 mm with adjuvant radiotherapy. Predictive accuracy of margin classification systems was compared by area under receiver-operating characteristic curves generated from logistic regression of 2½-year local recurrence-free survival and other standard tests of diagnostic accuracy. The Musculoskeletal Tumor Society and margin distance classifications performed similarly, both of which showed higher sensitivity and negative predictive value compared to the American Joint Committee on Cancer R classification. The prognostic power of close or positive margins in prediction models significantly increased when six or more slides were submitted for assessment of surgical resection margins. Surgical resection margins for soft tissue sarcoma should be reported using the Musculoskeletal Tumor Society classification or metric distance to the closest resection margin. Musculoskeletal Tumor Society wide/radical margins or tumor clearances of 5 mm (without adjuvant radiotherapy) or 1 mm (with adjuvant radiotherapy) appear to define the minimum safe surgical resection margins necessary to decrease the likelihood of local recurrence of high-grade pleomorphic sarcomas of the extremity or trunk.

Introduction tissue around the tumor [1]. The National Comprehensive Cancer Network continues to recommend adjuvant radio- The European Society for Medical Oncology recommends therapy for patients with soft tissue sarcoma resected with that soft tissue sarcomas of the extremity and trunk be close soft tissue (<1 cm from tumor) or positive resection excised with negative margins that include a rim of normal margins [2]. However, these recommendations are based on a limited number of studies of heterogeneous patient cohorts, particularly in regard to administration of adjuvant radiation therapy. Thus, the minimum margin distance Supplementary information The online version of this article (https:// doi.org/10.1038/s41379-019-0278-9) contains supplementary necessary to reduce the risk of local recurrence of high- material, which is available to authorized users. grade soft tissue sarcoma remains undefined. A major problem encountered when attempting to syn- * Justin M. M. Cates thesize the prior literature is the various classification [email protected] schemes used to report surgical resection margins for soft 1 Lancaster Christian Academy, Smyrna, TN 37167, USA tissue sarcoma (Table 1). The Enneking classification (since 2 Department of Pathology, Microbiology, and Immunology, adopted by the Musculoskeletal Tumor Society) has been a Vanderbilt University Medical Center, Nashville, TN 37232, USA clinically useful surgical definition of resection margin 1422 M. M. Cates, J. M. M. Cates

Table 1 Classification schemes used to report surgical resection margins for soft tissue sarcoma Margin Definitions classification scheme

AJCC R system R0 Grossly and microscopically negative R1 Microscopically positive R2 Grossly positive MSTS system Radical All normal tissue of involved anatomic compartments excised en bloc Wide Histologically non-reactive normal tissue at margin Marginal Pseudocapsule present at margin Fig. 1 Photomicrograph of the surgical resection margin of a high- grade pleomorphic sarcoma denoting Musculoskeletal Tumor Society Intralesional Tumor present at margin margin classifications (H&E, 40×) Margin distance Metric distance from edge of tumor to inked surgical resection margin AJCC American Joint Committee on Cancer, MSTS Musculoskeletal resected at our institution between 1995 and 2014 without Tumor Society prior neoadjuvant radiotherapy or chemotherapy. High- grade myxofibrosarcomas were excluded because this sarcoma subtype is associated with higher rates of local status since 1980 [3]. The College of American Pathologists recurrence than other sarcomas, most likely because of the instead mandates provision of a metric distance for report- tendency of the low-grade myxoid component to grow ing negative margins [4]. And the American Joint Com- along fibrous septa in subcutaneous tissues [7, 8]. Tumors mittee on Cancer R system simply reports margins as with a myxoid component were classified as undiffer- negative, microscopically positive, or grossly positive [5]. entiated pleomorphic sarcoma if <10% of the total exam- Which method of reporting status of surgical resection ined area was composed of hypocellular myxoid zones; margins is most accurate in predicting local recurrence has otherwise, the case was classified as a high-grade myxofi- not been directly analyzed. brosarcoma and excluded from the study. Dedifferentiated There is also a lack of evidence regarding the gross and liposarcomas were similarly excluded given the inherent histopathological assessment of the adequacy of surgical difficulty in differentially classifying resection margins resection margins, with one recent consensus practice involved by low-grade and high-grade sarcomatous com- guideline noting that “no available evidence-based data ponents and the better overall prognosis of these tumors [9]. addressed how to adequately assess margins” [6]. There- Resection specimens were prosected according to stan- fore, this study was performed to (1) determine the mini- dard technique [4]. Briefly, the widths of all surgical mum surgical resection margin distance necessary to reduce resection margins were evaluated grossly and metric dis- the risk of local recurrence in high-grade pleomorphic soft tances recorded; in addition to one representative section of tissue sarcomas treated with or without adjuvant radiation tumor per centimeter of its greatest dimension, all surgical therapy, (2) directly compare various margin classification resection margins ≤2 cm from tumor were inked and sam- schemes used in the literature, and (3) determine the number pled with one or more perpendicular sections. H&E-stained of tissue sections needed to adequately evaluate the status of slides were reviewed to confirm the histologic diagnosis and surgical resection margins by histopathologic examination. record the status of surgical resection margins according to American Joint Committee on Cancer and Musculoskeletal Tumor Society criteria [3, 5], as well as the margin distance Patients and methods and the tissue type composing the closest margin (pseudocapsule, fibroadipose, skeletal muscle, or dense regular Patient cohort connective tissue [fascia or periosteum]) (Fig. 1). Clinicopathologic data, including patient age, sex, tumor The study protocol was approved by the Institutional size, adjuvant therapy administered, and clinical outcomes Review Board at Vanderbilt University; a waiver of (local recurrence-free and disease-free survival) were informed consent was obtained. Surgical Pathology files abstracted from an institutional cancer registry and cross- were searched for primary, non-cutaneous, high-grade, referenced with electronic medical records. The primary pleomorphic soft tissue sarcomas of the extremities or trunk outcome measure was local recurrence. Median follow-up Surgical resection margin classifications for high-grade pleomorphic soft tissue sarcomas of the. . . 1423 for censored patients was 49 months (range, Table 2 Clinicopathologic characteristics of patient cohort (N = 166) 0.7–181 months). Recurrent disease (or death from sar- Variable N (%) coma) occurred in 77 patients (46%) a median of 8 months after surgical resection (range, 0.5–62 months). Local Sex recurrence developed in 22 patients (13%) a median of Female 72 (43) 14 months after surgical resection (range, 3–49 months). Male 94 (57) Histologic diagnosis Statistical analysis Undifferentiated pleomorphic sarcoma 126 (76) Leiomyosarcoma 24 (14) Associations and correlations between variables were Pleomorphic liposarcoma 14 (8) evaluated using standard bivariate methods. Subhazard Pleomorphic rhabdomyosarcoma 2 (1) ratios for local recurrence-free and disease-free survival Anatomic depth were estimated using competing risk regression. Multi- Deep soft tissue 136 (82) variate regression models were developed through stepwise Subcutaneous tissue 30 (18) elimination of variables in order of increasing z-score. Metastasis Tumor size and adjuvant radiation therapy were retained as None 147 (89) important covariates in all multivariate models because of Lymph node 2 (1) the known associations between these factors and local Lung 17 (10) – recurrence in soft tissue sarcoma [10 18]. Optimal tumor Adjuvant therapy clearance was determined using the Liu method (max- None 56 (34) fi imizing product of sensitivity and speci city), Youden Radiotherapy 100 (60) “ ” method (maximizing their sum), and the nearest method Chemotherapy 2 (1) (the point on receiver-operating characteristic curve closest Both 8 (5) to perfect sensitivity and specificity). Predictive accuracy of AJCC lymphovascular invasion margin classification systems was directly compared using 0 147 (88) areas under receiver-operating characteristic curves gener- 2 16 (10) ated from logistic regression of 2½-year local recurrence- 3 3 (2) free survival. All hypothesis tests were two-sided with α = 0.05. All statistical analyses were performed using Stata v15 AJCC R status (StataCorp, College Station, TX). R0 138 (83) R1 21 (13) R2 7 (4) Results MSTS margin status Wide/radical 96 (58) Clinicopathologic characteristics of the patient cohort (N = Marginal 42 (25) 166) are presented in Table 2. There was no missing data. Intralesional 28 (17) Average patient age was 65 year (SD 16 year; median 68 Tissue at margin year [IQR 54–77 year]). Mean tumor size was 10.4 cm (SD Pseudocapsule 42 (25) 5.7 cm; median 9 cm [IQR 5.8–15 cm]). Only 19 cases Skeletal muscle 35 (21) (11%) had evidence of nodal or distant metastasis at the time Adipose 21 (13) of surgical resection. Most patients (N = 108; 65%) received Fibroadipose 14 (8) adjuvant radiation therapy after surgical resection. Surgical Fascia 26 (16) resection margins were negative (American Joint Committee Tumor at margin 28 (17) on Cancer R0) in 138 cases (83%), with a median minimum – AJCC American Joint Committee on Cancer, MSTS Musculoskeletal margin distance of 1.4 mm (IQR 0.4 4.0 mm). Surgical Tumor Society resection margins were positive in 28 cases.

Pathologic assessment of surgical resection margins resection margins. As expected, there was a slight decrease in the number of slides submitted for evaluation of margins An average of 13 slides were submitted from resection with increasing tumor clearance (Spearman’s rs = ‒0.22; specimens for histopathologic examination (SD 5.3; median P = 0.009; Supplementary Fig. 1). Although there was no 12; IQR 9–15 cm), of which a mean of 6.5 (SD 2.8; median signiﬁcant association between submission of additional 6; IQR 5–8 cm) were dedicated to assessment of surgical slides examining tumor margins and documentation of a 1424 M. M. Cates, J. M. M. Cates

profound effect of adjuvant radiation therapy in decreasing the risk of local recurrence (Fig. 3 and Supplementary Table 2). For cases not treated with adjuvant radiation therapy, the American Joint Committee on Cancer R system appears to discriminate the level of risk rather well. In addition, adjuvant radiation therapy reduces the risk of an R1 margin to approximately that of an R0 resection. Fig- ure 3b shows that marginal and intralesional margins are essentially equivalent and that there is minimal risk of local recurrence with a wide or radical margin in the Muscu- loskeletal Tumor Society system. Also noteworthy is the marked reduction in the incidence of local recurrence after adjuvant radiation therapy for patients with marginal or intralesional margins, but not wide/radical margins. Fig. 2 Hazard ratios from parametric local recurrence-free survival analysis and odds ratios from logistic regression for local recurrence For assessment of tumor clearance, margin distance was within 2½ years of surgical resection associated with a positive arbitrarily categorized as positive, <1 mm, 1–2.9 mm, and resection margin (American Joint Committee on Cancer R1/R2; ≥3 mm. In general, increasing tumor clearance corresponds Musculoskeletal Tumor Society intralesional margin) by the number of to a decreased incidence of local recurrence (Fig. 3c). But sections submitted to evaluate surgical resection margins the cumulative incidence of local recurrence for the 17 patients with close (<1 mm) but negative surgical resection positive margin (odds ratio per additional slide = 1.08; 95% margins not treated with adjuvant radiation therapy is CI 0.95–1.24; P = 0.25; Supplementary Fig. 2), hazard unexpectedly low. Five of these patients did not receive ratios and odds ratios for local recurrence associated with a adjuvant radiation therapy because of coexistent metastatic positive resection margin (tumor present on inked surface) disease, three of whom died of sarcoma within 6 months of increased significantly when at least six tissue sections were surgical resection. Other patients were not treated with submitted to evaluate the resection margins (Fig. 2). Similar radiation therapy post-operatively presumably because of results were obtained when Musculoskeletal Tumor Society coexistent medical comorbidities, since another five patients margins or optimal margin distance cutoffs were used as the in this subgroup died of other causes within 18 months of independent variable instead of simply positive vs. negative surgical resection. However, the use of a competing risk resection margins (data not shown). regression model should account for these competing events. The low incidence of local recurrence in this group Competing risk regression of local recurrence of patients is therefore likely due to the limited follow-up (<24 months) of patients remaining at risk and an unex- Because patients who die of disease or other causes during pectedly low incidence of local recurrence in this small clinical follow-up are no longer at risk of local recurrence, a subgroup. competing risk regression model was used to assess risk Conversely, four out of 14 patients with resection mar- factors for this adverse event. None of the variables except gins between 1 and 2.9 mm in width recurred locally within for surgical resection margin status and tissue composition 15 months of surgical resection, resulting in an unexpect- of the surgical resection margin were statistically significant edly high cumulative incidence of local recurrence. All four in univariable analyses (Supplementary Table 1). Regard- cases were sampled adequately (≥6 slides submitted for less, given prior evidence that increasing tumor size and no examination of resection margin status). Notably, margin administration of adjuvant radiation therapy are associated widths in two of these cases were 1.1 and 1.2 mm, within with an increased probability of local recurrence, sub- 200 μm of being classified as <1 mm in width. Finally, it sequent analyses were adjusted for these important risk should be recalled that the sample sizes of the <1 mm and factors [10–18]. Initial exploratory analyses confirmed that 1–2.9 mm margin width subgroups not treated with post- adjuvant radiation therapy is an important confounding operative radiation therapy are small (N = 17 and N = 14, factor in assessment of adequacy of surgical resection respectively), and that the confidence intervals for these margins (Supplementary Fig. 3). None of the variables cumulative incidence functions overlap considerably. This violated the proportional hazards assumption as assessed by might also explain the counter-intuitive results graphically variance of coefficients over time (data not shown). represented in Fig. 3c. Similar findings were observed on Plots of cumulative incidence functions for local recur- conventional Kaplan–Meier local recurrence-free survival rence by each margin classification scheme adjusted for curves (data not shown). Nonetheless, there appears to be tumor size and adjuvant radiation therapy demonstrate the significant risk of local recurrence in patients not treated Surgical resection margin classifications for high-grade pleomorphic soft tissue sarcomas of the. . . 1425

Fig. 3 Cumulative incidence functions for local recurrence by each and administration of adjuvant radiotherapy. AJCC, American Joint surgical resection margin classification system adjusted for tumor size Committee on Cancer; MSTS, Musculoskeletal Tumor Society with post-operative radiation therapy if margin width is <5 22 cases [95%] vs. 10 of 10 cases [100%]; P = 0.49). mm in metric distance. In contrast, adjuvant radiation Conversely, soft tissue or dense regular connective tissue at therapy markedly reduces the incidence of local recurrence resection margin was associated with a significantly such that surgical resection margins of at least 1 mm are decreased incidence of local recurrence compared to a associated with a minimal risk of local recurrence. margin composed of pseudocapsular tissue (Table 3). A Similar results were obtained when the dependent vari- decreased risk of local recurrence was also observed for soft able studied in competing risk regression was sarcoma- tissue compared to pseudocapsule in competing risk specific survival (data not shown). regression analysis (Supplementary Table 1), but this difference failed to reach statistical significance after adjusting Effect of tissue composition of resection margin for margin distance, tumor size, and adjuvant radiation therapy (Supplementary Table 3). Assessment of the effect of tissue type comprising the resection margin by multivariable regression was precluded Local recurrence-free survival rates by surgical by the limited number of local recurrences in the subgroup resection margin status and adjuvant radiotherapy with negative margins. For patients not receiving adjuvant radiation therapy, there did not appear to be a significant Of the 22 patients who developed local recurrence, 21 difference in 2½-year local recurrence-free survival between (95%) did so within 2½ years of surgical resection. patients with closest margins composed of soft tissue Therefore, 2½-year local recurrence-free survival was cal- (fibroadipose or skeletal muscle) (13 out of 15 cases; 87%) culated for each margin classification system. Administra- or dense regular connective tissue (fascia or periosteum) (3 tion of adjuvant radiation therapy is a common practice at of 3 cases; 100%; P = 0.50). Similar findings were observed our institution, particularly when surgical resection margins for patients with soft tissue or dense regular connective are close or positive. Therefore, few cases with positive tissue at resection margin who did receive adjuvant radia- margins not subsequently treated with adjuvant radiation tion therapy (2½-year local recurrence-free survival, 21 of therapy were available for study. Nevertheless, plots of 1426 M. M. Cates, J. M. M. Cates

Table 3 2½-year local recurrence-free survival rates by tissue close (<1 mm) surgical resection margins. For patients with composition of surgical resection margin in patients who did or did margins ≥1 mm from tumor, the 2½-year local recurrence- not receive adjuvant radiotherapy free survival rate was 96% (25 of 26 cases) after radiation Tissue 2½- P (compared to therapy (P = 0.0086 compared to close or positive mar- year LRFS pseudocapsule) gins). Estimates of cutoff points for defining adequate Pseudocapsule, no RT 0/5 (0%) – resection margin width using three different empirical Soft tissue, no RTa 13/15 (87%) 0.004 methods were similar: 0.75 mm if adjuvant radiation ther- Fascia/ 3/3 (100%) 0.005 apy is given and 4.5 mm if not. For subsequent analysis, periosteum, no RT adequate margin width was therefore defined as ≥1mmif Pseudocapsule, RT 9/16 (56%) – adjuvant radiation therapy is given and ≥5mmifnot. Soft tissue, RTa 21/22 (95%) 0.003 One case recurred locally 14.5 months after surgical Fascia/periosteum, RT 9/9 (100%) 0.019 resection with a 4-mm (Musculoskeletal Tumor Society wide) margin. Although the tumor was 18 cm in greatest LRFS local recurrence-free survival, RT adjuvant radiotherapy dimension, only three slides were submitted for analysis of aSoft tissue (adipose, fibroadipose, and skeletal muscle) surgical resection margins, probably because the closest margin noted on gross examination was 4 mm of skeletal 2½-year local recurrence-free survival rates by surgical muscle. Adjuvant radiation therapy was not given to this resection margin status in patients who did or did not patient. Two other cases with Musculoskeletal Tumor receive adjuvant radiation therapy help to define adequate Society wide resection margins and ≥5 slides submitted to resection margins in these groups (Fig. 4 and Supplemen- evaluate resection margins recurred locally. One case with a tary Table 2). 0.7-mm margin composed of normal adipose tissue recurred For the American Joint Committee on Cancer R system 3 months after resection despite receiving adjuvant radiation (Fig. 4a), there were too few R1 or R2 cases that did not therapy. The other case recurred 6 months after resection receive post-operative radiation therapy for analysis. Base- with a 2.5-mm margin of skeletal muscle and no adjuvant line 2½-year local recurrence-free survival for cases with radiation therapy. No lymphovascular invasion was noted in R0 margins and no adjuvant radiation therapy was 70% (16/ the cases that recurred locally despite widely negative sur- 23 cases). For cases treated with radiation therapy after gical resection margins. surgical resection, local recurrence-free survival rates for R0 and R1 cases were equivalent (83%). The Musculoskeletal Predictive accuracy of surgical resection margin Tumor Society margin reporting system showed clear dif- reporting systems for 2½-year local recurrence-free ferences between wide/radical resections and marginal or survival intralesional resections regardless of whether radiation therapy was administered (Fig. 4b). Whereas 89% (16 of Logistic regression was performed with and without 18) patients with wide or radical margins without adjuvant adjustment for tumor size and administration of adjuvant radiation therapy were free of local recurrence 2½ years radiation therapy to assess the accuracy with which the after resection, all seven patients with intralesional or different margin classification systems predicted local marginal margins not treated with post-operative radiation recurrence within 2½ years of surgical resection (Fig. 5 and therapy recurred locally (P < 3.2×10−5). For patients Supplementary Table 4). Comparison of the resultant areas receiving radiation therapy after surgery, 2½-year local under receiver–operator characteristic curves suggest that, recurrence-free survival rates were 65% (20/31) for patients in isolation, Musculoskeletal Tumor Society margins (81%) with intralesional or marginal margins compared to 97% and margin distance (70%) are more accurate than Amer- (31/32) for patients with wide or radical margins ican Joint Committee on Cancer R status (57%; P = 0.0028 (P = 0.0011). and P = 0.0083, respectively). However, once adjuvant Administration of adjuvant radiation therapy clearly radiation therapy and tumor size are accounted for, these affects determination of an adequate resection margin when differences in predictive accuracy were no longer statisti- defined by margin distance as well (Fig. 4c). For patients cally significant (P = 0.14). not receiving post-operative radiation therapy, a resection margin distance of <3 mm resulted in a 2½-year local Diagnostic accuracy of surgical resection margin recurrence-free survival rate of 43% (6 of 14 cases) com- classifications pared to 91% (10 of 11 cases) for patients with a margin width of at least 3 mm (P = 0.013). Adjuvant radiation Each margin reporting system was then dichotomized at therapy increased the 2½-year local recurrence-free survival optimal cutoff points and assessed as a diagnostic test for rate to 69% (25 of 36 cases) for patients with positive or prediction of local recurrence. American Joint Committee Surgical resection margin classifications for high-grade pleomorphic soft tissue sarcomas of the. . . 1427

Fig. 4 Crude 2½-year local recurrence-free survival rates (with 95% not receive adjuvant radiotherapy. Predicted probabilities and 95% confidence intervals) by (A) American Joint Committee on Cancer confidence intervals from logistic regression analysis are also plotted (AJCC) R system, (B) Musculoskeletal Tumor Society (MSTS) mar- for margin distance gin classification, and (C) margin distance in patients who did or did

Fig. 5 Receiver–operator characteristic curves for each surgical resection margin classiﬁcation system generated from (A) univariable logistic regression and (B) multivariable logistic regression adjusting for tumor size and administration of adjuvant radiotherapy. AJCC, American Joint Committee on Cancer; MSTS, Musculoskeletal Tumor Society 1428 M. M. Cates, J. M. M. Cates

Fig. 6 Diagnostic performance of optimally dichotomized surgical resection margin classiﬁcation systems (A) Sens., sensitivity; Spec., speciﬁcity; PPV, positive predictive value; NPV, negative predictive value); (B) LR+, positive likelihood ratio; Inv.LR–, inverse (reciprocal) of negative likelihood ratio; DOR, diagnostic odds ratio [LR +/LR–]). AJCC, American Joint Committee on Cancer; MSTS, Musculoskeletal Tumor Society

on Cancer R status was classified as negative (R0) or of [neo]adjuvant therapy) for definitive conclusions to be positive (R1 or R2). Musculoskeletal Tumor Society mar- made regarding the optimal width of surgical resection gins were classified as adequate (wide/radical) or inade- margins. Moreover, the various margin classifications and quate (intralesional or marginal). Adequate margin distance definitions used apparently befuddled some consensus was defined as ≥1 mm with adjuvant radiation therapy and experts, since the European Society for Medical Oncology ≥5 mm without adjuvant radiation therapy. While tests of guidelines for reporting surgical resection margins are self- diagnostic accuracy were generally similar for the Muscu- contradictory; assessment of Musculoskeletal Tumor loskeletal Tumor Society and margin distance classifica- Society margin status is not possible given only the “status tions, both showed evidence of superiority over the of inked margins and the distance between tumor edge and American Joint Committee on Cancer R system in terms of the closest inked margins” [1]. Therefore, this study was sensitivity, negative likelihood ratio, and negative pre- performed to determine the minimum margin width neces- dictive value as demonstrated by non-overlapping 95% sary to reduce the risk of local recurrence in a relatively confidence intervals (Fig. 6 and Supplementary Table 5). homogenous cohort of high-grade pleomorphic soft tissue Of the 21 cases classified with American Joint Com- sarcomas of the extremity or trunk not treated with neoad- mittee on Cancer R0 margins but considered inadequate in juvant therapy while controlling for the confounding effects the Musculoskeletal Tumor Society system (marginal mar- of adjuvant radiation therapy and tumor size. gins), 12 (57%) recurred within 2½ years. Similarly, local The optimal Musculoskeletal Tumor Society resection recurrence developed in 14 of 34 (41%) R0 cases resected margin in this study was determined to be wide or radical with inadequate margin width. Fifteen cases were resected regardless of whether tumors were treated with adjuvant with inadequate margin width but were considered wide or radiation therapy. This result in agreement with Enneking’s radical in the Musculoskeletal Tumor Society classification; original assessment and other subsequent studies of the three (20%) of these cases recurred locally. Only two cases Musculoskeletal Tumor Society system in classifying with marginal resection margins were resected with margins resection margins for soft tissue sarcoma [13, 28]. With the considered adequate by metric distance criteria. increased use of adjuvant radiation therapy, it was later suggested that the local recurrence rates associated with both wide/radical or marginal/intralesional resection mar- Discussion gins could be significantly reduced [19, 22, 29, 31]. More recent studies have seemingly abandoned the Enneking Many prior studies have attempted to define the minimum concept of resection margins in favor of reporting margin margin of surgical resection required to reduce the risk of distance. Unfortunately, the Vanderbilt cohort of high-grade local recurrence for soft tissue sarcoma (Table 4) pleomorphic sarcomas not treated with neoadjuvant therapy [8, 11, 13, 14, 19–33]. Unfortunately, the patient cohorts in is too small to analyze margin distance as a continuous most of these studies were too heterogeneous (with inclu- variable [34]. Therefore, margin distance was categorized sion of recurrent tumors, re-excisions of previously arbitrarily for statistical analysis. In this manner, a resection incompletely excised tumors, tumors with markedly dif- margin width of at least 5 mm was determined to be ade- ferent biological potential [i.e., well-differentiated lipo- quate if no adjuvant radiation therapy is administered, but sarcoma or other low-grade sarcomas], and variable usage this could be reduced to 1 mm if post-operative radiotherapy Surgical resection margin classifications for high-grade pleomorphic soft tissue sarcomas of the. . . 1429

Table 4 Prior studies examining surgical resection margins in soft tissue sarcomas primarily of the extremities or trunk Author Classiﬁcation N LR Metric LR rate Adjuvant Cohort (%) therapy heterogeneity

Enneking, [28] Crude LR None Recurrent tumors Radical 24 1 4.2 Prior excision Wide 12 3a 30.0 Subtypes Marginal 4 2 50.0 Grade Intralesional 0 0 – Alho [29] Crude LR Subtypeb Wide 145 8 5.5 Marginal+RT 21 2 9.5 Marginal 19 7 36.8 Bell [30] Crude LR RT Subtype + or <1 mm 48 24 50.0 Grade ≥1 mm 52 4 7.7 Stotter [31] 3-yr LR ±RT Subtypeb Wide/radical 24 3 11.0 Grade +RT Wide/radical 17 5 29.0 IL/marginal 73 25 34.0 +RT IL/marginal 61 34 56.0 Herbert [32] 5-yr LR ±RT (92%) Subtypeb >5 mm 37 0 0.0 Grade ≤5 mm 10 1 20.0 Neoadjuvant RT (8%) Positive 19 6 55.0 Pisters [33] 5-yr LR ±Brachytherapy Recurrent tumors >1 mm+BRT 63 8 12.7 Subtype >1 mm 72 20 27.8 Grade <1 mm+BRT 15 5 33.3 <1 mm 14 5 35.7 Trovik [19] 5-yr LR ±RT IL/marginal 64 25 39.0 IL/marginal 119 28 24.0 +RT Wide 198 50 25.0 Radical 10 0 0.0 McKee [11] 5-yr LR ±RT Subtypeb ≥10 mm 53 8 16.0 Grade 3–9 mm 32 10 31.0 1–2 mm 13 5 39.0 Positive 13 6 46.0 Gronchi [20] 10-yr LR ±RT Subtypeb >1 mm 556 72 13.0 Grade ≤1 mm 86 25 29.0 Dickinson [21] 5-yr LR ±RT Subtypeb ≥20 mm 12 0 0 Grade 10–19 mm 51 5 9 ±Neoadjuvant RT 5–9mm 33 2 5 1430 M. M. Cates, J. M. M. Cates

Table 4 (continued) Author Classiﬁcation N LR Metric LR rate Adjuvant Cohort (%) therapy heterogeneity

1–4mm 61 3 4 <1 mm 59 10 17 Positive 36 8 22 Jebsen [22] 5-yr LR ±RT (356) Subtypeb Wide+RT NS NS 7.0 Grade Wide NS NS 20.0 ±Neoadjuvant RT Marginal+RT NS NS 18.0 Marginal NS NS 43.0 Intralesional NS NS 38.0 +RT Intralesional NS NS 74.0 Liu [23] 5-yr LR ±RT Subtypeb ≥30 mm 9 0 0.0 Grade 20–29 mm 21 2 9.0 10–19 mm 40 1 3.0 5–9 mm 23 10 42.0 1–4 mm 36 15 42.0 Positive 52 37 71.0 Gronchi [8] 5-yr LR ±RT Subtype R0 874 87 10.0 Grade R1-close 11 2 20.0 R1-positive 106 29 27.0 R2 6 2 33.0 Novais [24] 5-yr LR ±RT Subtype >20 mm 35 0 0.0 ±Neoadjuvant therapy 2.1–20 mm 164 2 2.0 + or ≤2 mm 49 5 12.0 Maretty- 5-yr LR ±RT Recurrent tumors Nielsen [13] Wide 636 76 12 Subtypeb IL/Marginal 237 59 25 Grade Willeumier Crude LR ±RT Subtype [14] >2 mm 38 3 8.0 ≤2 mm 75 22 30.0 Positive 12 6 50.0 Kainhofer [25] 5-yr LR ±RT Prior excision ≥1 mm 83 10 12 Subtype <1 mm 16 6 38 Positive 14 5 37 Harati [26] 5-yr LR ±RT Subtypeb >5 mm, No RT NS NS 31.6 Grade 1–5 NS NS 32.2 mm, No RT ≤1 mm, No RT NS NS 31.4 >5 mm, RT NS NS 28.4 1–5 mm, RT NS NS 21.1 ≤1 mm, RT NS NS 29.1 Surgical resection margin classiﬁcations for high-grade pleomorphic soft tissue sarcomas of the. . . 1431

Table 4 (continued) Author Classiﬁcation N LR Metric LR rate Adjuvant Cohort (%) therapy heterogeneity

5-yr LR R0, No RT 341 124 36 R1, No RT 24 17 71 R0, RT 249 71 29 R1, RT 19 10 54 Gundle [27] 5-yr LR ±RT Subtype R0 1908 114 6.0 Grade R1 (+) 278 47 17.0 Prior excision R1 (+ or <1 726 72 10.0 ±Neoadjuvant RT mm) R2 26 10 38.0 BRT brachytherapy, IL intralesional, LR local recurrence, NS not stated, RT radiotherapy, R0/R1/R2 American Joint Committee on Cancer R classification a High-grade sarcomas only b Including well-differentiated liposarcoma is given. Other studies have reported similar results for this study because tumor bed re-excision specimens were tumors treated with adjuvant radiation therapy excluded and the observed close/positive margins could not [8, 20, 21, 25, 30, 33, 35]. While other groups have pre- be correlated to those of clinical concern from available sented data suggesting that surgical resection margins operative reports with certainty. should be at least 10 mm in width to reduce the risk of local Other clinical and pathologic variables evaluated (histo- recurrence [11, 23], surgical resection margins as close as 2 logic subtype of sarcoma, anatomic depth [superficial vs. mm have been reported to be safe in other cohorts [14, 24]. deep soft tissue], distant metastasis, or lymphovascular But significant fractions of these patient populations were invasion) did not significantly affect the risk of local treated either with neoadjuvant therapy, post-operative recurrence in this case series, but this may be due to the radiation therapy, or both, confounding interpretation of limited numbers cases within these various subgroups. the extent of margin width on local recurrence rates. Although it is possible that these factors may affect the Additional anatomic and clinical factors may influence potential for local recurrence, their effects, if any, appear the adequacy of margin width as well, such as the tissue minor in comparison to other more important factors such composition of the margin and the clinical setting of close as surgical resection margin status, administration of adju- or positive margins. Enneking discussed the potential role vant radiation therapy, and tumor size. of anatomical barriers in reducing the risk of local recur- Another goal of this study was to determine what margin rence in soft tissue sarcomas early on, a concept subse- classification system should be used in reporting the status quently evaluated by the Scandinavian Sarcoma Group and of surgical resection margins. Direct comparisons of the Japanese Orthopaedic Association [3, 36, 37]. Although the American Joint Committee on Cancer R system, Muscu- type of tissue present at the resection margin did not appear loskeletal Tumor Society classification, and margin distance to have a significant effect in this study, the numbers of methods have not been previously reported. Both the cases available for study were too few to account for other Musculoskeletal Tumor Society system and margin distance important prognostic factors such as margin distance, tumor reporting classifications showed increased accuracy for size, and adjuvant radiation therapy. predicting local recurrence within 2½ years of surgical Gerrand and colleagues first assessed the impact of the resection than the American Joint Committee on Cancer R type of positive surgical resection margin on recurrence system, even after adjusting for critical confounding factors. (a planned close/positive margin adjacent to a critical ana- In addition, both the Musculoskeletal Tumor Society system tomic structure, a positive margin incurred during re- and margin distance reporting classifications showed overall excision of the tumor bed after a previous unplanned better diagnostic performance in predicting local recurrence excision, or unplanned/unexpected positive margins) [38]. within 2½ years of surgical resection than the American Subsequently known as the Toronto Margin Context Clas- Joint Committee on Cancer R system when dichotomized at sification, this system has since been validated in follow-up optimal cutoff values. The negative predictive value of an studies [16, 27]. This classification could not be assessed in R0 margin in the American Joint Committee on Cancer R 1432 M. M. Cates, J. M. M. Cates system is clearly inferior to more conservative margin radiation therapy) or 1 mm (with adjuvant radiation therapy) reporting systems that consider negative but close margins appear to define the minimum safe surgical resection mar- (i.e., marginal margins or tumor clearance ≤1 mm with gins necessary to decrease the likelihood of local recurrence radiation therapy or ≤5 mm without radiation therapy) as of high-grade pleomorphic soft tissue sarcomas of the indicative of an increased risk of local recurrence. There- extremity or trunk. Using these definitions, the Muscu- fore, at our institution, we now report both the Muscu- loskeletal Tumor Society and margin distance classifica- loskeletal Tumor Society margin classification as well as the tions are more predictive of clinical outcomes than the metric distance and tissue composition of the closest American Joint Committee on Cancer R system, which resection margin, since we believe that the American Joint suffers from low sensitivity and negative predictive value. Committee on Cancer system is less informative in pre- Surgical resection margins for soft tissue sarcoma should be dicting the risk of local recurrence. carefully examined at the time of gross inspection, with a Finally, preliminary evidence is provided here to define total of six or more sections submitted from margins <2 cm the minimum number of tissue sections necessary to ade- from tumor. quately evaluate the status of surgical resection margins by histopathologic examination. Philosophical arguments Compliance with ethical standards aside, the practice of “proving a negative” or failing to Conflict of interest The authors declare that they have no conflict of reject the null hypothesis, H0: “the resection margins are negative” is basically a statistical sampling problem. The- interest. oretically (and ignoring the possibility of false positives, Publisher’s note: Springer Nature remains neutral with regard to such as when excess ink is identified on tumor either incised jurisdictional claims in published maps and institutional affiliations. by the prosector or when the tumor capsule inadvertently slips during prosection), only one section would be ade- References quate if it unequivocally documents the presence of a positive margin. But how many sections should be sub- 1. Casali PG, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot mitted before we accept (or fail to reject) this null hypoth- S, et al. 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